U.S. patent application number 11/991771 was filed with the patent office on 2009-05-28 for formulations of indanylamines and the use thereof as local anesthetics and as medication for chronic pain.
This patent application is currently assigned to BRIDGE PHARMA, INC.. Invention is credited to A.K. Gunnar Aberg, Keith Johnson.
Application Number | 20090137628 11/991771 |
Document ID | / |
Family ID | 37900325 |
Filed Date | 2009-05-28 |
United States Patent
Application |
20090137628 |
Kind Code |
A1 |
Aberg; A.K. Gunnar ; et
al. |
May 28, 2009 |
Formulations of Indanylamines and the Use Thereof as Local
Anesthetics and as Medication for Chronic Pain
Abstract
Dermal and mucosal formulations of
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, characterized by
rapid dermal and mucosal absorption and long duration of
therapeutic activity are provided. Also provided are solutions of
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine for injection,
characterized by short onset time and long duration of activity.
Formulations containing both
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine and capsaicin are
also provided.
Inventors: |
Aberg; A.K. Gunnar;
(Sarasota, FL) ; Johnson; Keith; (Durham,
NC) |
Correspondence
Address: |
Nields, Lemack & Frame, LLC
176 E. Main Street, Suite #5
Westborough
MA
01581
US
|
Assignee: |
BRIDGE PHARMA, INC.
Sarasota
FL
|
Family ID: |
37900325 |
Appl. No.: |
11/991771 |
Filed: |
September 22, 2006 |
PCT Filed: |
September 22, 2006 |
PCT NO: |
PCT/US2006/037070 |
371 Date: |
June 16, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60719904 |
Sep 23, 2005 |
|
|
|
60839783 |
Aug 24, 2006 |
|
|
|
Current U.S.
Class: |
514/319 |
Current CPC
Class: |
A61K 9/12 20130101; A61K
9/0014 20130101; A61P 25/00 20180101; A61K 9/0034 20130101; A61K
9/02 20130101; A61K 9/0031 20130101; A61K 9/7015 20130101; A61K
9/0019 20130101 |
Class at
Publication: |
514/319 |
International
Class: |
A61K 31/4458 20060101
A61K031/4458; A61P 25/00 20060101 A61P025/00 |
Claims
1. A dermal formulation for inducing relief of pain or for
preventing pain, comprising a therapeutically effective amount of
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an optically
active isomer thereof, or a pharmaceutically acceptable salt
thereof, dissolved in one or more solvents in which said piperidine
is soluble, together with an anti-solvent in an amount sufficient
to reduce the solubility of said
2-[(2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine in said one or
more solvents such that upon application of said formulation to the
skin of a patient, said solvent evaporates to form a saturated
solution of said 2-[2-(N-Phenyl-N-2-indanyl)aminoethyl]piperidine
facilitating the penetration of said
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine into the skin.
2. A formulation according to claim 1 that contains from 0.1
percent to 30 percent of
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an optically
active isomer thereof, in its free base form.
3. A formulation according to claim 1 that contains from 0.1
percent to 30 percent of
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an optically
active isomer thereof, as a pharmaceutically acceptable salt.
4. A formulation according to claims 1 or 2, wherein the said one
or more solvents is a member selected from the group consisting of
ethanol, dimethylsulfoxide, isopropanol, propylene carbonate,
propylene glycol, decylmethylsulfoxide, N,N-dimethyl acetamide,
2-pyrrolidone, N,N-dimethyl formamide, 1-methyl-2-pyrrolidone,
5-methyl-2-pyrrolidone, 1,5-methyl-2-pyrrolidone,
1-ethyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, oleic acid,
laurocapram (azone), limonene, cineole, diethyl-m-toluamide (deet),
sodium dodecylsulfate, trimethyl phosphine oxide,
tetrahydrofurfuryl alcohol, glycerol, monolaurate, methyl oleate,
and propylene glycol monolaurate, and mixtures thereof.
5. A formulation according to claims 1 or 2, further comprising one
or more non-ionic surfactants selected from the group consisting of
dimethylsulfoxide, ethanol, isopropanol, propylene glycol, glycerol
monolaurate, propylene glycol monolaurate, sorbitan monolaurate,
sorbitan sesquioleate, polysorbate 20, peg-40 stearate,
steareth-20, poloxamer 185.
6. A formulation according to claim 1 that contains
dimethylsulfoxide in a concentration ranging from 1 percent to 100
percent.
7. A formulation according to claim 1, where the formulation is a
solution, cream, ointment, lotion, spray, aerosol, foam or
paste.
8. A formulation according to claim 1, wherein said anti-solvent is
water.
9. A formulation according to claim 1 that is delivered to the skin
by the use of a vehicle or device suitable for dermal or epidermal
delivery.
10. A formulation according to claim 1, further comprising
capsaicin in a concentration from 0.001 percent to 5 percent.
11. A formulation according to claim 9 in the form of a solution,
cream, ointment, lotion, gel, spray, aerosol, foam, or paste.
12. A pharmaceutical composition for induction of local anesthesia,
comprising as an active agent a local anesthetic inducing effective
amount of 2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an
optically active isomer thereof, or a pharmaceutically acceptable
salt thereof, dissolved in a pharmaceutically acceptable solvent,
and further comprising an anti-solvent in an amount sufficient to
reduce the solubility of said
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine in said solvent
such that upon application of said composition to the skin of a
patient, said solvent evaporates to form a saturated solution of
said 2-[2-(N-Phenyl-N-2-indanyl)aminoethyl]piperidine, facilitating
the penetration of said
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine into the skin.
13. The pharmaceutical composition of claim 12, wherein said
anti-solvent is water.
14. The pharmaceutical composition of claim 12, wherein said
piperidine is in the form of its free base.
15. A method of increasing the rate of penetration of
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine through the skin
of a patient, comprising formulating a composition of said
piperidine in a pharmaceutically acceptable solvent with an
anti-solvent in an amount sufficient to reduce the solubility of
said piperidine in said solvent, and applying said composition to
said skin.
16. The method of claim 15, wherein said anti-solvent is water.
17. The method of claim 15, wherein said piperidine is in the form
of its free base.
18. The method of claim 15, wherein said piperidine is in the form
of a pharmaceutically acceptable salt.
19. The method of claim 15, wherein said piperidine is in the form
of its dihydrochloride salt.
20. The method of claim 15, wherein said composition further
comprises capsaicin.
Description
[0001] This application claims priority of U.S. Provisional
Application No. 60/719,904 filed Sep. 23, 2005 and U.S. Provisional
Application No. 60/839,783 filed Aug. 24, 2006, the disclosures of
which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Local anesthetics are used to prevent expected painful
conditions and to treat patients suffering from pain, including
neuropathic pain. Local anesthetics are used in both human and
veterinary medicine.
[0003] The present invention refers to new formulations containing
the local anesthetic compound
2-[2-(N-Phenyl-N-2-indanyl)aminoethyl]piperidine ("LAC-34") and
other therapeutic entities, such as for example capsaicin and
carefully selected concentrations of various excipients, such as
for example solvents, carriers, penetration enhancers, occlusive
agents, and emollients. In order to obtain pain-free drug delivery
and analgesic activity of long duration, capsaicinoids such as
capsaicin may be included in the new formulations described
here.
[0004] LAC-34 is an extremely potent local anesthetic that also has
analgesic effects. Thus, LAC-34 is useful as a local anesthetic and
as an analgesic drug. Since LAC-34 was found to have very unusual
solubility properties, standard formulations for this drug are not
useful and new formulations containing LAC-34 have now been
developed. This was particularly the case for dermal formulations
of LAC-34.
[0005] The mechanism of action of local anesthetic drugs and
formulations thereof for the treatment of acute pain, such as for
example pain caused by surgery, is a temporary inhibition of nerve
conduction in afferent sensory nerves, which is caused by
inhibition of sodium channels in said neuronal tissues.
[0006] The mechanism of action of drugs and formulations thereof
for the treatment of chronic pain, such as for example neuropathic
pain, is not just to offer temporary inhibition of afferent nerve
conduction in afferent nerves, but also to offer analgesic activity
to the patient, which may be achieved by numerous and largely
unknown mechanisms.
[0007] The indanylamine compound of Formula I has now been found to
have such analgesic activities and the formulations of the present
invention have been found to facilitate the transport of said
chemical entities from the application site to the biophase, where
the compounds can exert therapeutic activity.
[0008] In combination with certain other compounds that influence
the function of sensory nerves, such as for example capsaicin, a
useful synergism and a surprising potentiation of the therapeutic
benefits has been found with regard to the effects on acute pain
and particularly with regard to the effects on chronic pain.
[0009] The term "topical anesthesia" is in this document defined as
local anesthesia of mucosal membranes, such as for examples those
of the eye, the ear, the mouth, the nose, the rectal area and the
urogenital tract. The term "dermal anesthesia" is in this document
defined as local anesthesia of the skin, including the foreskin.
The term "infiltration anesthesia" refers to anesthesia of minor
nerves and nerve endings by infiltrating the tissues containing
such nerves or nerve endings with a formulation containing a local
anesthetic compound. The term "nerve block" in this document refers
to the blockade of nerve transmission by administering a
formulation of local anesthetic compound close to said nerve. The
term "local anesthesia" in this document includes all anesthesia of
afferent and efferent nerves and includes "dermal anesthesia",
topical anesthesia" "infiltration anesthesia" and "nerve
blocks"
[0010] The terms "neuropathic pain" and "neuropathy" refer to a
group of chronic painful conditions characterized by pain
originating from neural damage. This affects more than 10 million
people in the United States alone. This group of patients includes
those with a wide variety of primary conditions, which precipitate
the debilitating symptoms of thermal and mechanical hyperalgesia
that are typical of neuropathic pain.
[0011] The terms "analgesic" and "analgesia" as used here refer to
relief of pain by drugs that offer analgesic effects, regardless of
their mechanism(s) of action.
[0012] Although the field of neuropathic pain is large both in
terms of patient numbers, suffering, and economic impact on
individuals and society, the understanding of neuropathic pain is
not complete. The first annual International Conference on the
Mechanisms and Treatment of Neuropathic Pain was held in 1998 and
in the same year, two publications in the Journal of the American
Medical Association focused the interest on the use of the
anti-seizure drug gabapentin to treat pain in patients with
neuropathic pain.
[0013] The various conditions of neuropathic pain have presented
clinicians with multiple challenges ranging from difficulties in
diagnosis to a lack of effective treatments. When the diagnosis has
been made, clinicians typically resort to treating neuropathic pain
with old medications that were originally developed for other
indications. Due to the lack of effective medications, treatment
decisions are often made on a trial and error basis and therapeutic
agents, such as tricyclic antidepressants, gabapentin, lidocaine
patches, narcotics such as oxycontin, and painkillers such as
tramadol are being used. The development of improved experimental
models and a better understanding of the pathophysiology of the
different neuropathic pain conditions has recently made the
rational testing possible of compounds that may be useful for
neuropathic pain. Additionally, clinical evaluation of these and
existing agents in well-defined patients groups will allow
treatment guidelines to further improve. Better knowledge of
various types of neuropathic pain will allow the scientific
community to select target indications of drugs for neuropathic
pain, such as for example neuropathic low back pain, diabetic
neuropathic pain, HIV-related neuropathic pain, shingles and
various other hyperalgesic and/or neuropathic conditions. Thus,
gabapentin and similar compounds are being tried in patients
suffering from Neuropathic Low Back Pain (NLBP), while lidocaine
patches and capsaicin may offer temporary and more short-acting
relief of Diabetic Neuropathic Pain and Shingles. However, and as
mentioned above, NSAIDs, narcotics, and even antidepressants are
presently used by patients and doctors who desperately try to find
medication to decrease the intensity of neuropathic pain.
Parenteral injections or dermal application of formulations
containing capsaicin or similar agents that may induce degeneration
of interneurons in the substantia gelatinosa of the dorsal spinal
cord offer promise, particularly if the severe acute pain in
association with the drug administration can be eliminated.
[0014] Thus, the drug described herein, LAC-34, is useful both as a
local anesthetic and as medication for patients suffering from
neuropathic pain. When used as a local anesthetic (and particularly
as a dermal anesthetic), it is important that the formulation of
LAC-34 offers a short onset time of anesthesia. On the other hand,
when used as medication for chronic neuropathic pain, the emphasis
is on long duration of analgesia rather than fast onset of acute
pain relief.
[0015] The preparation of effective, efficient formulations
containing LAC-34 has proved to be challenging due to the unusual
solubility profile of this active moiety. Thus, the free base of
LAC-34 has low solubility in water and is therefore not very useful
for injection. Several pharmaceutically acceptable salts exist that
have improved water solubility, such as for example the
di-hydrochloride salt of LAC-34. However, in preclinical studies it
has now been found that the free base of LAC-34 offers advantageous
dermal anesthesia when compared with various salt forms.
[0016] In accordance with the present invention, dermal
compositions have now been formulated, such as creams, gels and
aerosols containing LAC-34 free base, but also containing various
salts of LAC-34, ranging from salt forms with very low water
solubility, such as for example the monohydrochloride salt, to salt
forms with high water solubility, such as for example the
dihydrochloride salt. The new formulations express (a) local
anesthetic activities, making them useful as dermal and topical
anesthetics and (b) analgesic activities, making them useful in the
treatment of chronic pain, in particular for the treatment of
neuropathic pain. The dermal formulations typically contain
pre-determined concentrations of LAC-34 free base, optionally in
combination with one or more solvents, carriers, penetration
enhancers, occlusive agents, and/or emollients. The combination of
excipients provides means of delivering the drug from highly
concentrated (e.g., supersaturated) compositions through skin where
the penetration barriers are decreased by the formulations, while
the formulations also may repair barrier damage, protect the skin,
and hydrate the skin.
[0017] The combination of oral or parenteral medication for
neuropathic pain with one or more drugs of the present invention
can result in a potentiated therapeutic activity. Thus LAC-34
and/or capsaicin dosed dermally or parenterally may be combined
with a drug such as for example gabapentin (Neurontine.RTM.),
phenyloin (Dilantin.RTM.) or carbamezepine (Tegretol.RTM.) that is
dosed orally to the patient.
SUMMARY OF THE INVENTION
[0018] This invention relates to formulations containing LAC-34, to
methods of using said formulations as local anesthetics, methods of
inducing local, topical or dermal anesthesia, methods of
administering the formulations, particularly to a localized region
of a patient, and for the treatment of pain and in particular,
chronic pain.
[0019] The chemical structure of LAC-34 is:
##STR00001##
[0020] The chemical compound LAC-34
(2-[2-(N-Phenyl-N-2-indanyl)aminoethyl]piperidine) exists as a free
base as well as numerous salts. The compound has pharmacological
properties that render said compounds to be useful as local
anesthetics to inhibit acute pain (U.S. Pat. No. 6,413,987 B1,
incorporated herein by reference) and as analgesic medication to
prevent and to treat pain, in particular chronic pain, such as
neuropathic pain. It achieves short onset time and long duration of
local anesthesia, topical anesthesia and dermal anesthesia.
[0021] It has now been found that the solubility profile of LAC-34,
as the free base, can be effectively reduced by the addition of an
anti-solvent, such as water, in an amount sufficient to entice the
LAC-34 active agent, upon dermal or topical application, to readily
penetrate the skin or mucous membrane of a patient and reach the
nerve structure in a sufficient concentration to achieve a
therapeutic effect. Surprisingly, the anti-solvent does not just
have a dilution effect on the formulation; even small amounts of
anti-solvent reduce the solubility of the free base dramatically,
such that the formulation approaches saturation or becomes
saturated, enhancing the propensity of the active agent to come out
of solution and enter the skin or mucous membranes. Indeed, the
solubility of the free base in various solvents is so high that the
free base is virtually ineffective as a dermal or topical
anesthetic agent when dissolved in such solvents in the absence of
an anti-solvent. The anti-solvent therefore increases the rate at
which the LAC-34 penetrates the skin or mucous membranes of a
patient compared to identical formulations but devoid of the
anti-solvent.
[0022] Formulations for parenteral injections of solutions
containing LAC-34, contain said compound preferably as a
water-soluble salt, such as for example the dihydrochloride salt in
a solution that may also contain preservatives, penetration
enhancers and vasoconstrictors.
[0023] In combination with other compounds, such as capsaicin, a
surprising potentiation of the local anesthetic activity has been
found.
[0024] In combination with compounds, such as capsaicin, a
surprising and very significant improvement of the therapeutic
activity in subjects suffering from neuropathic pain is now
evident.
[0025] Prevention and treatment of (a) acute pain, such as for
example pain caused by surgical treatment, including circumcision,
vaccination, venopuncture, intravenous cannulation and (b) chronic
pain, such as for example neuropathic pain, in particular dermal
neuropathic pain, using the formulations of this invention may be
achieved by applying said formulations containing LAC-34 on the
skin or by injecting solutions of LAC-34 to infiltrate biological
tissues in the vicinity of nerves.
[0026] The compound LAC-34 can also be used as oral therapy for
patients suffering from pain, such as for example neuropathic pain.
Conventional oral dose forms may be used and controlled release
oral formulations may have advantages over regular tablets or
capsules. The oral dose of LAC-34 will have to be titrated for the
weight and age of the patient, the severity of the condition and
the results that may be expected. Oral doses of between 3 mg and
300 mg may be useful, but lower doses may also be used,
particularly in combination with dermal or parenteral formulations
containing LAC-34 or a combination of LAC-34 and capsaicinoids.
[0027] When used to treat cardiac arrhythmias-atrial or ventricular
arrhythmias--LAC-34 can be administered transdermally, parenterally
or orally. The doses and the frequency of drug administration
depends on the size and age of the patient, the severity of the
condition and the results that may be expected. Dermal or topical
doses of 10 to 500 mg, intravenous doses of from 1 to 100 mg and
oral doses of 5 to 200 mg, administered one to four times daily may
be useful for patients suffering from cardiac arrhythmias.
[0028] Formulations of LAC-34, intended for dermal and topical
administration, preferably contain LAC-34 in its free base form.
However, several pharmaceutically acceptable salt forms, such as
for example the mesylate or the monohydrochloride and other salts
with limited water solubility but suitable solubility in various
other excipients, may be used for dermal and mucosal administration
of LAC-34, and formulations similar to those disclosed here can
also be used for various salt forms of LAC-34 and for the optically
active isomers of LAC-34.
[0029] The optical isomers of LAC-34 have certain advantages over
the racemic compound LAC-34 as disclosed in U.S. Pat. No.
6,413,987. Statements regarding the racemate in this document are
in general valid also for the optically active isomers of LAC-34.
Thus instead of the racemic mixture LAC-34, the optically active
isomers thereof can in most cases be used in the formulations
described herein. In some cases, some modifications may be needed
of the formulations described here, as obvious to those skilled in
the art or as determined using routine laboratory procedures by
those skilled in the art.
[0030] It was unexpectedly found that LAC-34 exerts analgesic
activity in animal models of neuropathic pain and this activity was
potentiated by the addition of capsaicin that per se has both
algesic and analgesic effects. In addition, the acute and severe
pain caused by parenteral or dermal administration of capsaicin is
eliminated by administration of a composition, containing LAC-34 as
the single therapeutic agent or a formulation containing both
LAC-34 and capsaicin. The present invention presents that capsaicin
can either be conveniently administered together with LAC-34 in the
same formulation, or the two therapeutically active entities can be
administered separately.
[0031] Thus, the present invention provides formulations for
treating humans and animals with (A) dermal and topical anesthetic
and parenteral local anesthetic formulations containing LAC-34, (B)
dermal and topical analgesic and parenteral analgesic formulations
containing LAC-34, (C) dermal and topical anesthetic and parenteral
local anesthetic formulations containing both LAC-34 and capsaicin,
(D) dermal and topical and parenteral analgesic formulations
containing both LAC-34 and capsaicin. The term LAC-34 in this
context includes, where appropriate, the optically active isomers
of LAC-34, and suitable salts and solvates thereof.
BRIEF DESCRIPTION OF THE DRAWING
[0032] FIG. 1 is a graph of peak area versus concentration of
LAC-34.
DETAILED DESCRIPTION OF THE INVENTION
Dermal and Topical Formulations of Lac-34 Useful for Dermal and
Topical Anesthesia and for Analgesia after Dermal or Topical
Application
[0033] The dermal and topical formulations of the present invention
contain the compound LAC-34 or an optically active isomer thereof
in concentrations effective for inducing anesthesia, and
particularly in concentrations of about 0.05% to about 20%,
preferably 0.1% to 10%. Dermal formulations containing LAC-34 may
be applied on the skin one to four times daily, depending on the
severity of the disease, the condition of the patient and the
effect that is sought. Dermal formulations containing a
capsaicinoid such as capsaicin contain the capsaicinoid in
concentration between about 0.001% and about 5%, preferably 0.01%
to 1.0%. As realized by those skilled in the art, higher or lower
concentrations of both LAC-34 and a capsaicinoid may prove to be
useful and, under certain circumstances, even preferred. Dermal
formulations containing LAC-34 in combination with a selected
capsaicinoid, such as for example capsaicin, may be applied on the
skin one to four times daily, depending on the severity of the
disease the condition of the patient and the effect that is
sought.
[0034] Solutions for dermal application contain one or more
excipients in addition to LAC-34 or an optically active isomer of
LAC-34. A partial list of suitable pharmaceutically acceptable
excipients is shown in Table 1.
TABLE-US-00001 TABLE 1 Examples of excipients, evaluated for their
usefulness in formulations of LAC-34 (including solutions, gels and
creams/lotions) Excipient Description Function Capric/caprylic
Semi-polar Oil phase for emulsion, triglycerides oil emollient
Dibutyl adipate Semi-polar Solvent, emollient oil DMSO Solvent
Solvent, penetration enhancer Ethanol Volatile Solvent, penetration
solvent enhancer Hexylene glycol Solvent Solvent Isopropyl
Semi-polar Oil phase for emulsion, myristate oil emollient
Isopropanol Volatile Solvent, penetration solvent enhancer Mineral
oil Oil Oil phase for emulsion, semi-occlusive Pentane Oil None,
used as model propellant Propylene Solvent Solvent carbonate
Propylene glycol Solvent Solvent, penetration enhancer, humectant
Triacetin Semi-polar Solvent oil Water Water Solvent, vehicle base,
humectant, anti-solvent
[0035] As known by those skilled in the art, practically all
chemical entities have limited solubility in one or a few of the
key formulation excipients. Surprisingly, this was not the case for
LAC-34. This compound was very soluble in all the excipients
screened, with the exception of mineral oil, as shown in Table 2
(EXAMPLE 2). This made it highly unlikely to find useful standard
dermal and topical formulation for LAC-34.
[0036] The addition of an anti-solvent to the LAC-34 formulation
was found to efficiently and effectively lower the solubility of
the LAC-34 in the excipient, and thereby enhance its ability to
penetrate the skin or mucous membranes of a patient. Water is an
excellent anti-solvent for LAC-34 in various solvents. The
decreased solubility is not merely due to the decreased
concentration of the solvents, as is obvious to those skilled in
the art of pharmaceutical formulations, from the very significant
decrease of the solubility when only small amounts of water are
added. Thus, water did not merely dilute the solvents, but water
acted as an anti-solvent for LAC-34 in the investigated
excipients.
[0037] Solvents and penetration enhancers are useful in various
formulations when combined with LAC-34, including: capric/caprylic
triglycerides, dibutyl adipate, DMSO, ethanol, hexylene glycol,
isopropyl myristate, isopropanol, mineral oil, pentane, propylene
carbonate, propylene glycol, triacetin, water,
decylmethylsulfoxide, N,N-dimethyl acetamide, 2-pyrrolidone,
N,N-dimethyl formamide, 1-methyl-2-pyrrolidone,
5-methyl-2-pyrrolidone, 1,5-methyl-2-pyrrolidone,
1-ethyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, oleic acid,
laurocapram (azone), limonene, cineole, diethyl-m-toluamide (deet),
sodium dodecylsulfate, trimethyl phosphine oxide,
tetrahydrofurfuryl alcohol, glycerol, monolaurate, methyl oleate,
and propylene glycol monolaurate. The preferred concentration of
solvents in dermal formulation will range from 0.4 percent to 96
percent, and will depend on which additional excipients are being
used and the concentration of said additional excipients.
[0038] Many penetration enhancers are also surfactants and based on
the current findings of physico-chemical properties of LAC-34, the
following selected anionic surfactants may pair with LAC-34 in
various formulations: sodium dodecylsulfate, dioctyl sodium
sulfosuccinate, triethanolamine lauryl sulfate and ammonium lauryl
sulfate. The preferred concentration of surfactants in dermal
formulation of LAC-34 will range from 0.4 percent to 96 percent,
and will depend on which additional excipients are being used and
the concentration of said additional excipients.
[0039] Those skilled in the art will appreciate that certain
non-ionic surfactants may be useful in various dermal formulations.
Examples of such surfactants are: glycerol monolaurate, propylene
glycol monolaurate, sorbitan monolaurate, sorbitan sesquioleate,
polysorbate 20, peg-40 stearate, steareth-20, poloxamer 185. In
addition, selected cationic surfactants, such as for example cetyl
pyridinium chloride and benzalkonium chloride may also pair with
LAC-34. Zwitterionic surfactants, such as for example lecithin may
also prove to be useful.
[0040] Various "solubilizers" may be used and are generally used to
improve the drug in the selected vehicle and/or improve the dermal
penetration and/or act as humectants. Examples of "solubilizers"
are neutral methacrylic acid esters, polyhydric alcohols such as
propylene glycol or polyethylene glycol, surfactants such as sodium
lauryl sulphate, vitamin E or combinations of various
solubilizers.
[0041] Permeation enhancers will improve the dermal penetration and
are usually lipophilic solvents, such as for example
dimethylsulfoxide, or a surfactant such as for example sodium
lauryl sulfate or tween, oleic acid, oleic acid/PG, octyl dimethyl
para-amino benzoic acid, a polyhydric alcohol such as propylene
glycol or combinations of various penetration enhancers.
[0042] Plasticizers may be added to improve the softness of the
dermal film and may consist of for example PG, polyethylene glycol,
dimethylisosorbide acetyltributyl citrate, triethyl citrate or
combinations of various plasticizers.
[0043] Humectants can be added to promote the retention of moisture
in the skin and examples of humectants are polyhydric alcohols,
such as for example butylene glycol, propylene glycol, polyethylene
glycol, sorbitol and glycerol, or combinations of various
humectants.
[0044] Anti-solvents can be added to decrease the solubility of
molecules in various solvents and examples of anti-solvents are for
example ethylene glycol, diethylene glycol, glycerol,
1,2-propandiol, isopropanol and water. In the case of LAC-34, water
was found to be an excellent anti-solvent as shown in Table 4 and
there was no need to test any synthetic anti-solvents (EXAMPLE 4)
The concentrations of anti-solvents needed will depend on the
concentration(s) of the solvent or solvents in the formulation and
the efficacy of the selected anti-solvent in the selected
solvent(s). Depending on the specific circumstances, the
concentrations of the anti-solvent may range from one percent of
the concentration of the solvent(s) up to 90 percent of the
concentration of a specific solvent when other solvents are
present. Most often it is enough to use an anti-solvent in
concentrations that range from 1 percent to 50 percent of a
solvent, but higher concentrations of the anti-solvent may be
needed as obvious to those skilled in the art of making dermal and
topical formulations.
[0045] Suitable polymers may be included in the formulation to form
a stable film on a surface, such as skin, when applied. The film is
stable if resistant to rubbing. Preferred film-forming polymers
include methacrylic polymers and copolymers as well as acrylic
polymers and copolymers, such as for example a copolymer of
dimethylamine ethyl methacrylate and a neutral methacrylic acid
ester, ammonio methacrylate copolymer type A or type B, methacrylic
acid copolymer type A or type B, hydroxypropylcellulose,
hydroxyethylcellulose, methyl or ethyl cellulose, cellulose
acetate, polyvinyl alcohol and povidone. The porosity of the film
is considered important and can be increased by adding watersoluble
compounds, such as for example propylene glycol, polyethylene
glycol, sodium lauryl sulfate, cetomacrogol or transcutol, or
combinations thereof.
[0046] Where the formulation is an aerosol, the propellant used may
be any pharmaceutically acceptable propellant. Preferred
propellants include for example butane, isobutene, propane,
dimethylether or other hydrocarbons, dichlorodifluoromethane,
trichloro-monofluoromethane, dichloro-fluoroethane,
monochloro-difluoromethane, difluoroethane,
dichloro-tetrafluoroethane, heptafluoropropane, tetrafluoroethane
or other fluorocarbones, or a compressed gas, such as for example
carbon dioxide or nitrogen.
[0047] Aerosol formulations of the present invention cause low skin
irritation-particularly in comparison with patches. Aerosol
formulations and aerosol dispensers are easy of use and relatively
inexpensive to manufacture.
[0048] The aerosol dispenser can be a conventional aerosol can with
a conventional metered spray aerosol valve. The pump dispenser can
be a conventional bottle or can with a conventional metered spray
pump.
[0049] The composition is typically applied over a fixed,
predetermined area of the skin and is usually from 10 cm.sup.2 to
25 cm.sup.2 per actuation. Multiple actuations will be used to
cover larger areas, such as for example to patients suffering from
shingles or other forms of neuropathic pain.
[0050] A dermal or topical formulation of LAC-34 may include a high
concentration of DMSO or a similar penetration enhancer. Animal
experience have indicated that the vehicle may contain as much as
100% DMSO, although most biological studies were performed with
vehicle containing 95% DMSO+5% water or less DMSO
Suspension Formulations
[0051] LAC-34 and its salts, or optically active isomers thereof,
could also be prepared as suspensions in dermal formulations. In
these formulations, LAC-34 would be present as fine to coarse
particles with suitable stabilizers and other excipients. The term
"nanosuspensions" refers to colloidal dispersions of
sub-micron-size particles of a drug, which are most often
stabilized by one or more surfactants in the suspension. Sub-micron
size particles of a drug such as LAC-34 may also be dispersed in
lipidic carriers. Nanosupensions are of interest for LAC-34 since
such suspension may be supersaturated with LAC-34, Such a
supersaturated suspension being stable until intentionally
destabilized to form saturated or supersaturated dermal
formulation. Suspension formulations with particles of LAC-34, its
salts or optically active isomers, wherein said particle sizes may
range from coarse to submicron size, are encompassed in the present
invention.
Devices
[0052] LAC-34 delivery can be facilitated using devices such as a
dermal patch or an injector. The patch could deliver LAC-34, or an
optically active isomer thereof, to the skin by passive diffusion
or by using an active delivery system, such as for example
iontophoresis or sonophoresis. Injectors could have a needle or be
needless. The doses of LAC-34 used in dermal or transdermal patches
will be similar to the doses of lidocaine, presently used in
Lidoderm.RTM. patches. Due to the low tissue toxicity of LAC-34,
higher concentrations, such as 5% to 10% may also prove to be
useful in a patch formulation containing LAC-34. Dermal or
transdermal patches may be applied one or more times daily.
Needless injectors will have obvious advantages, such as for
example in selected patients, such as children, and may be used in
connection with dermal pain (insect bites, etc) or in preparation
for expectedly painful injections with a regular syringe or in
preparation for dermal surgical procedures.
[0053] In general, the compositions of the present invention are
prepared by dissolving the active ingredient, LAC-34, as a racemate
or as a single isomer, in either its free base or in a salt form,
in a pharmaceutically acceptable solvent, such as DMSO, at room
temperature, and adding an anti-solvent, such as water, to the
solution. Optional ingredients such as capsaicinoids, permeation
enhancers, solubilizers, plasticizers, propellants (in the case of
aerosols) may be added before or after the anti-solvent. Specific
information for various compositions of formulations are given in
the following examples.
EXAMPLE 1
Development of Analytical Method
[0054] Racemic LAC-34 as a free base (Lot # GLS-L7-163) was used
for this study. All solvents were USP, NF, ACS Reagent, or HPLC
(acetonitrile) grade. The free base of LAC-34 can exist as a white
powder or as a yellowish-brown crystal or oil.
[0055] A liquid's capability to solubilize LAC-34 was screened by
adding a known mass of LAC-34 to a known volume/mass of liquid.
Saturation solubility was measured by adding an excess of drug
substance and allowing the suspension to equilibrate while stirring
for 2-3 days. A sample of the suspension was filtered though a 0.2
.mu.m PTFE membrane followed by dilution (if required) and HPLC
analysis. For several mixed solvent systems that included water, a
known mass of drug substance was dissolved in a known mass of
solvent(s). This solution was then titrated with water while
stirring until the solution became cloudy. All solubility
measurements were conducted at room temperature (approximately
21-23.degree. C.).
[0056] HPLC analysis was performed with a HP 1050 system (He
degasser, quaternary pump, auto-injector, and variable wavelength
detector). The column heater was manufactured by Waters. Data
collection and analysis was performed using Chemstation.RTM.
software.
Results and Discussion
HPLC Analytical Methodology.
[0057] HPLC analytical methodology was developed. Four solutions of
LAC-34 (8.1 mcg/mL to 0.98 mg/mL) plus a blank were injected in
triplicate. Good linearity for the response is shown in FIG. 1.
[0058] The relative standard deviations of peak areas for all
LAC-34 solutions were less than 0.5%. The blanks assayed before and
after LAC-34 solutions showed no significant drug level, which
demonstrated there was no carry-over.
[0059] Based on the reproducibility of results over three orders of
magnitude in LAC-34 concentrations, no carry-over, and good
linearity in the anticipated concentration range, the analytical
method was considered acceptable to measure LAC-34 solubility.
EXAMPLE 2
[0060] Various excipients were tested for their capability to
dissolve LAC-34, free base. Some results from these screening tests
are shown in Table 2.
TABLE-US-00002 TABLE 2 Solubility of LAC-34 free base - screening
tests Solubility of LAC-34 (base; Excipient mg/mL) Polar Ethanol
>86 Isopropyl alcohol >79 Propylene glycol >76 Benzyl
alcohol >100 Propylene carbonate >78 Hexylene glycol >75
Semi-polar/non-polar Dibutyl adipate >79 Isopropyl myristate
>78 Isopropyl palmitate 50-100 Mineral oil <50
[0061] With the exception of mineral oil, LAC-34 could be dissolved
in high concentrations in all the solvents tested. LAC-34 has a
yellowish-brown color when it exists as a glass and solutions in
Table 2 were yellowish-brown.
[0062] When tested at 4.degree. C., 20% LAC-34 in benzyl alcohol
was still a solution, 5% LAC-34 in propylene glycol was a gel, 5%
LAC-34 in isopropyl myristate was a suspension, 5% LAC-34 in
isopropyl palmitate was a solid, 5% LAC-34 in isopropyl alcohol was
a suspension and cetyl alcohol was a solid (melting
point=49.3.degree. C.).
EXAMPLE 3
Tests of Saturation Solubility in Selected Solvents
[0063] The saturation solubility of LAC-34 was measured in
capric/caprylic triglycerides (CCT), dimethylsulfoxide (DMSO),
ethanol, isopropanol, isopropyl myristate (IPM), pentane, propylene
glycol (PG), and water. CCT and IPM were selected for further work
since they can function as emollients and oily vehicles in creams.
DMSO is a solvent and a penetration enhancer. Ethanol and
isopropanol are volatile solvents and rapid evaporation of a
solvent like ethanol and isopropyl alcohol may be important for
minimizing therapeutic onset time. Propylene glycol has multiple
functions in dermal formulations, the most important of which are
solubilization and penetration enhancement. Some results from the
saturation studies with LAC-34 are shown in Table 3.
TABLE-US-00003 TABLE 3 Saturation solubility of LAC-34 free base in
key solvents for dermal drug delivery. LAC-34 Solubility, Solvents
mg/mL Capric/caprylic 195 triglycerides (CCT) 215 DMSO >2,000
Ethanol >526, <2,000 Isopropanol 184 Isopropyl myristate
(IPM) 149 Propylene glycol (PG) 0.005 Water
All of the solvents, with the exception of water, were able to
dissolve large quantities of LAC-34. LAC-34, as the free base, was
very soluble also in DMSO. Both IPM and CCT, which are semi-polar
emollient oils, had also high solubilization capacity for LAC-34.
Propylene glycol (PG), which has multiple actions for dermal drug
delivery (see Table 1), was also able to solubilize significant
quantities of LAC-34. Ethanol had a very high capacity to dissolve
LAC-34 and was never saturated. The value for ethanol in Table 3
was obtained by adding 0.25 g of ethanol to 0.498 g of LAC-34,
which rapidly resulted in a homogeneous solution. After observing
this phenomenon with ethanol, 0.125 g of isopropanol was added to
0.25 g of LAC-34. Surprisingly, isopropanol was not able to
solubilize the drug until the isopropanol level was 0.225 g. This
was approximately 526 mg/mL. Since ethanol is very volatile and has
a surprisingly high solubilization capacity for LAC-34, having a
portion of isopropanol in a dermal formulation for LAC-34 may be
useful in creating saturated solutions on the skin. Additional
opportunities exist to create super-saturated solutions on the skin
by using crystallization inhibitors, such as for example a povidone
(Lipp R. selection and use of crystallization inhibitors for
matrix-type transdermal drug-delivery systems containing sex
steroids. J. Pharm Pharmacol, 1998, 50: 1343-1349), such as for
example polyvinyl pyrrolidone (Povidone, Merck Index 12.sup.th Ed.,
7879).
EXAMPLE 4
Tests of Anti-Solvents/Binary Solvent Mixtures
[0064] Due to the very high solubility of LAC-34 free base in
numerous volatile solvents, it was determined to be necessary to
find and add an anti-solvent in order to reach saturation of the
solutions of LAC-34. The efficacy of water is an anti-solvent for
LAC-34 free base was investigated in the present studies. Table 4
shows the impact of water on solubility in some important
solvents.
TABLE-US-00004 TABLE 4 Solubility of LAC-34 (in mg/mL) in mixtures
of solvent and water. % Water PG Ethanol DMSO 0 149 >2000 215 1
139 -- -- 2.5 104 -- -- 5 63 -- .gtoreq.100** 10 29 -- -- 15 -- 63*
-- 20 8.7 33* -- 30 -- 7.0* -- 50 0.37 -- 1.7 75 0.075 -- -- 90 --
-- 0.45 *Titrated from an ethanol/LAC-34 solution with water
**previous tests
[0065] As shown in Table 4, water was an excellent anti-solvent for
LAC-34 in various solvents. This surprising finding was considered
to be important since water is an endogenous molecule found in all
mammals and additional toxicity testing of synthetic anti-solvents
will therefore not be needed. The decreased solubility is not
merely due to the decreased concentration of the solvents, as is
obvious to those skilled in the art of pharmaceutical formulations,
from the very significant decrease of the solubility when small
amounts of water is added. Thus, water did not merely dilute the
solvents, but water acted as an anti-solvent for LAC-34 in the
investigated excipients.
EXAMPLE 5
Tests of Ternary solvent mixtures
[0066] Laboratory studies have now demonstrated the compatibility
of combinations of various solvents with water as an anti-solvent.
Thus, the solubility of 150 mg of LAC-34 free base in a mixture of
1 ml of polyethylene glycol and 1 ml of ethanol was dramatically
decreased to 5.5% (w/w) by the presence of only 0.6 ml of the
anti-solvent (water).
[0067] Suitable dermal formulations of LAC-34 include (1)
solutions, (2) gels, (3) creams or lotions, (4) ointments, (5)
suppositories (6) aerosols or (7) sprays.
EXAMPLE 6
Aqueous and Non-Aqueous Solutions
TABLE-US-00005 [0068] TABLE 6 Solutions of LAC-34, and the
optically active isomers thereof for dermal and topical
applications: % w/w of Component Formulation RS, R-- or S-LAC-34
0.1 to 20.0 (base) Ethanol 5.0 to 25.0 Propylene glycol 10.0 to
75.0 Antioxidants.sup.1 0.0 to 0.1 Preservatives.sup.2 0.0 to 0.5
Penetration 0.0 to 50.0 enhancers.sup.3 Water/buffer q.s.
.sup.1Examples: BHA, BHT .sup.2Examples: ethyl paraben, propyl
paraben, imidurea .sup.3Examples: DMSO, diethylene glycol monoethyl
ether, n-decyl methyl sulfoxide, dimethylacetamide, laurocapram
(Azone .RTM.), dimethylformamide; sucrose monooleate,
N-methyl-2-pyrrolidine (Pharmasolve .RTM.), oleic acid
[0069] The solutions will preferably contain from 0.1 percent to 30
percent of 2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an
optically active isomer thereof, in its free base form or as a
pharmaceutically acceptable salt.
[0070] Capsaicin (0.01% to 1.0%; W/w) can be included in these
formulations to obtain prolonged relief from pain and in particular
from neuropathic pain. The compound LAC-34 will inhibit or decrease
the initial pain caused by capsaicin. Other capsaicinoids, such as
dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin
homodihydrocapsaicin can also be used in analogous amounts, as can
the partial capsaicin receptor antagonist capsazepine and other
compounds that directly increase the inflow of calcium through the
neuron membranes or indirectly influence ionic flow through neuron
membranes through activation of the vanilloid subtype-1 receptor
(such as for example resiniferatoxin),
EXAMPLE 7
Methods of Manufacture: Solutions for Dermal and Topical
Application
[0071] Dissolve LAC-34 in the solvent where it has the highest
solubility (e.g., ethanol or isopropyl alcohol). Add additional
solvents with preservatives, penetration enhancers, and
antioxidants; then mix until well combined. Add water with buffers
as needed. Mix until well combined then pack into appropriate
container/closure system. The racemic form of LAC-34 or an
optically active isomer thereof can be used. The free base or a
suitable salt form can be used. The solutions will preferably
contain from 0.1 percent to 30 percent of
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an optically
active isomer thereof, in its free base form or as a
pharmaceutically acceptable salt.
EXAMPLE 8
Aqueous or Non-Aqueous Gels
[0072] A dermal gel formulation of LAC-34 can contain PG, water or
buffer, ethanol, a polymer, and optionally another penetration
enhancer. Since the amount of water in the formulation may be
small, polymers that can gel non-aqueous system such as
hydroxypropylcellulose (HPC) or hydroxyethylcellulose (HEC) can be
used. In experiments with HEC, this excipient was found not only to
ably gel the systems, but surprisingly, HEC was also found to be
able to stabilize supersaturated solutions of LAC-34 on the skin's
surface. As persons skilled in the art will realize, other
topically acceptable gelling agents and may also prove to be useful
in gels containing LAC-34.
TABLE-US-00006 TABLE 7 Gels containing LAC-34 base for dermal
applications: % w/w of Component Formulation RS--, R-- or S-LAC-
0.1 to 20.0 34 Ethanol 5.0 to 25.0 Propylene glycol 50.0 to 75.0
Polymer.sup.1 0.5 to 3.0 Antioxidants.sup.2 0.0 to 0.3
Preservatives.sup.3 0.0 to 0.5 Penetration 0.0 to 20.0
enhancers.sup.4 Water/buffer q.s. .sup.1Examples:
Hydroxypropylcellulose, hydroxyethylcellulose, carbomer
.sup.2Examples: BHA, BHT .sup.3Examples: Methyl paraben, propyl
paraben, imidurea .sup.4Examples: DMSO, diethylene glycol monoethyl
ether, n-decyl methyl sulfoxide, dimethylacetamide, laurocapram
(Azone .RTM.), dimethylformamide, sucrose monooleate,
N-methyl-2-pyrrolidine (Pharmasolve .RTM.), and oleic acid
[0073] The gels will preferably contain from 0.1 percent to 30
percent of 2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an
optically active isomer thereof, in its free base form or as a
pharmaceutically acceptable salt.
[0074] Capsaicin (0.01% to 1.0%; w/w) can be included in these
formulations to obtain prolonged relief from pain and in particular
from neuropathic pain. The compound LAC-34 will inhibit or decrease
the initial pain caused by capsaicin. Other capsaicinoids, such as
dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin
homodihydrocapsaicin can also be used in analogous amounts, as can
the partial capsaicin receptor antagonist capsazepine and other
compounds that directly or indirectly influence ionic flow in
neuron membranes.
EXAMPLE 9
Methods of Manufacture: Gels
[0075] Dissolve LAC-34 in the solvent where it has the highest
solubility (e.g., ethanol or isopropyl alcohol). Add additional
solvents with preservatives, penetration enhancers, and
antioxidants then mix until well combined.
[0076] Disperse polymer under appropriate conditions recommended by
the manufacturer. Add water with buffers (if required) and
neutralizing bases as needed. Mix until well combined and thickened
then pack into appropriate container/closure system.
[0077] The racemic form of LAC-34 or an optically active isomer
thereof can be used. The free base or a suitable salt form can be
used. The gels will preferably contain from 0.1 percent to 30
percent of 2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an
optically active isomer thereof, in its free base form or as a
pharmaceutically acceptable salt.
EXAMPLE 10
Emollient Creams and Lotions
[0078] The surprisingly high solubility of LAC-34 in emollient oils
was exploited to develop elegant cream formulations. When the
oil-phase was approximately 55%, a 10% LAC-34 cream could be made
with IPM or CCT. A penetration enhancer could also be included.
TABLE-US-00007 TABLE 8 Creams containing LAC-34 base for dermal
applications: % w/w of Component Formulation RS--, R-- or S-LAC-34
0.1 to 20.0 Capric/Caprylic 0.0 to 50.0 Triglycerides Isopropyl
myristate 0.0 to 50.0 Propylene glycol 0.0 to 25.0 Surfactant 1.0
to 5.0 Polymer.sup.1 0.5 to 3.0 Antioxidants.sup.2 0.0 to 0.3
Preservatives.sup.3 0.0 to 0.5 Penetration enhancers.sup.4 0.0 to
30.0 Water/buffer q.s. .sup.1Examples: Hydroxypropylcellulose,
hydroxyethylcellulose, carbomer, xanthan gum .sup.2Examples: BHA,
BHT .sup.3Examples: Methyl paraben, propyl paraben, imidurea
.sup.4Examples: DMSO, diethylene glycol monoethyl ether, n-decyl
methyl sulfoxide, dimethylacetamide, laurocapram (Azone .RTM.),
dimethylformamide, sucrose monooleate, N-methyl-2-pyrrolidine
(Pharmasolve .RTM.), and oleic acid
[0079] The emollient creams or lotions will preferably contain from
0.1 percent to 30 percent of
2-[(2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an optically
active isomer thereof, in its free base form or as a
pharmaceutically acceptable salt.
[0080] Capsaicin (0.01% to 1.0%; w/w) can be included in these
formulations to obtain prolonged relief from pain and in particular
from neuropathic pain. The compound LAC-34 will inhibit or decrease
the initial pain caused by capsaicin. Other capsaicinoids, such as
dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin and
homodihydrocapsaicin can also be used in analogous amounts, as can
the partial capsaicin receptor antagonist capsazepine and other
compounds that directly or indirectly influence ionic flow in
neuron membranes.
EXAMPLE 11
Methods of Manufacture: Creams
[0081] Combine oils, semi-polar oils, antioxidants, penetration
enhancers, and surfactants and heat to 60-75.degree. C. (Phase A).
Combine polar solvents, preservatives, water, buffer salts, and
polymer and heat to 60-75.degree. C. (Phase B) Dissolve LAC-34 in
Phase A then immediately
add Phase A to Phase B with rapid stirring. High-shear mixing for a
specified time may also be required. Cool the mixture while
stirring to 30-50.degree. C. If the polymer requires a basic
substance to thicken (e.g., sodium hydroxide or triethanolamine),
add the base. Once product is sufficiently thickened and cool
(.ltoreq.35.degree. C.), stop stirring and begin packing the
product into the appropriate container closure system.
[0082] The racemic form of LAC-34 or an optically active isomer
thereof can be used. The free base or a suitable salt form can be
used. The emollient creams or lotions will preferably contain from
0.1 percent to 30 percent of
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an optically
active isomer thereof, in its free base form or as a
pharmaceutically acceptable salt.
EXAMPLE 12
Ointments for Dermal, Rectal and Vaginal Application
[0083] While the unexpectedly high solubility of LAC-34 base in
practically all excipients (not water) complicated the formulation
of dermal solutions, gels and cream containing LAC-34, the high
solubility of LAC-34 in "oily" excipients like IPM and mineral oil
can also bee seen as an advantage since such excipients tend to be
non-irritating and may be suited to an emollient cream formulation
for extended use and for ointments (i.e., hemorrhoids, shingles,
etc.).
TABLE-US-00008 TABLE 9 Ointments (and non-irritant creams)
containing LAC- 34 for dermal and rectal use % w/w of Component
Formulation RS--, R--, or S-LAC- 1.0 to 20.0 34 Propylene glycol
2.5 to 10.0 Microcrystalline 5.0 to 30.0 wax White wax (bees 0.0 to
20.0 wax) Surfactants 0.5 to 5.0 Antioxidants.sup.1 0.0 to 0.1
Penetration 0.0 to 20.0 enhancer.sup.2 Mineral oil q.s.
.sup.1Examples: BHA, BHT .sup.2Examples: DMSO, diethylene glycol
monoethyl ether, n-decyl methyl sulfoxide, dimethylacetamide,
laurocapram (Azone .RTM.), dimethylformamide, sucrose monooleate,
N-methyl-2-pyrrolidine (Pharmasolve .RTM.), and oleic acid
[0084] The ointments and non-irritant creams will preferably
contain from 0.1 percent to 30 percent of
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an optically
active isomer thereof, in its free base form or as a
pharmaceutically acceptable salt.
Capsaicin (0.01% to 1.0%; w/w) can be included in these
formulations to obtain prolonged relief from pain and in particular
from neuropathic pain. The compound LAC-34 will inhibit or decrease
the initial pain caused by capsaicin. Other capsaicinoids, such as
dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin
homodihydrocapsaicin can also be used in analogous amounts, as can
the partial capsaicin receptor antagonist capsazepine and other
compounds that directly or indirectly influence ionic flow in
neuron membranes.
EXAMPLE 13
Methods of Manufacture: Ointments
[0085] Combine waxes, oils, and semi-polar oils, and antioxidants
and heat to 60-75.degree. C. (Phase A). Combine LAC-34 with solvent
(e.g., propylene glycol) and penetration enhancer (if used) and
heat to 60-75.degree. C. (Phase B). Add Phase B to Phase A and mix
under high shear while cooling. Once ointment thickens, stop high
shear and mix with low shear until product is sufficiently cool
(.ltoreq.35.degree. C.), stop stirring and begin packing the
product into the appropriate container closure system.
[0086] The racemic form of LAC-34 or an optically active isomer
thereof can be used. The free base or a suitable salt form can be
used.
[0087] The ointments and non-irritant creams will preferably
contain from 0.1 percent to 30 percent of
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an optically
active isomer thereof, in its free base form or as a
pharmaceutically acceptable salt.
EXAMPLE 14
Suppositories for Rectal or Vaginal Applications
[0088] Suppositories are useful for the treatment of vaginal and
rectal pain, particularly hemorrhoidal pain.
TABLE-US-00009 TABLE 10 Suppository formulations containing LAC-34
base for rectal or vaginal applications. % w/w of Component
Formulation RS--, R-- or S-LAC-34 0.1 to 20.0 Antioxidants.sup.1
0.0 to 0.3 Preservatives.sup.2 0.0 to 0.5 Penetration
enhancers.sup.3 0.0 to 10.0 Suppository maxtrix.sup.4 q.s.
.sup.1Examples: BHA, BHT .sup.2Examples: Methyl paraben, propyl
paraben, imidurea .sup.3Examples: DMSO, diethylene glycol monoethyl
ether, n-decyl methyl sulfoxide, dimethylacetamide, laurocapram
(Azone .RTM.), dimethylformamide, sucrose monooleate,
N-methyl-2-pyrrolidine (Pharmasolve .RTM.), and oleic acid
.sup.4Polyethylene glycol (molecular weights 200 to 20,000),
hydrogenated vegetable oil (e.g., Wecobee .RTM. S, Wecobee .RTM.
FS
[0089] The suppositories will preferably contain from 0.1 percent
to 30 percent of 2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine,
or an optically active isomer thereof, in its free base form or as
a pharmaceutically acceptable salt.
[0090] Capsaicin (0.01% to 1.0%; w/w) can be included in these
formulations to obtain prolonged relief from pain and in particular
from neuropathic pain. The compound LAC-34 will inhibit or decrease
the initial pain caused by capsaicin. Other capsaicinoids, such as
dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin and
homodihydrocapsaicin can also be used in analogous amounts, as can
the partial capsaicin receptor antagonist capsazepine and other
compounds that directly or indirectly influence ionic flow in
neuron membranes.
EXAMPLE 15
Methods of Manufacture: Suppositories
[0091] Melt suppository matrix material (i.e., polyethylene glycol
or partially hydrogenated vegetable oil) then dissolve LAC-34 in
the melt. Fill melt into mold, cool, and un-mold. Pack
suppositories in appropriate container/closure system.
[0092] The racemic form of LAC-34 or an optically active isomer
thereof can be used in concentrations from about 0.1 percent to
about 20 percent. The free base or a suitable salt form can be
used.
[0093] The suppositories will preferably contain from 0.1 percent
to 30 percent of 2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine,
or an optically active isomer thereof, in its free base form or as
a pharmaceutically acceptable salt.
EXAMPLE 16
Aerosol Sprays (Pump or Propellant Driven)
[0094] In addition to the solubility experiments shown in Table 3,
the solubility of LAC-34 (base) was also investigated using pentane
since this is an example of low molecular weight hydrocarbons,
commonly used to model a GRAS aerosol propellant such as butane.
The result is shown below. The surprisingly very high solubility of
LAC-34 in pentane indicates that hydrocarbon aerosol propellants
such as butane will be useful for drug delivery to the skin by
aerosol.
TABLE-US-00010 TABLE 11 Saturation solubility of LAC-34 in pentane.
Solvent LAC-34 Solubility, mg/ Pentane 150* *Pentane evaporates
rapidly and is difficult to weigh. This value, therefore, is not
exact.
[0095] Thus, since LAC-34 is very soluble in both volatile solvents
and low molecular weight hydrocarbons, an aerosol formulation of
LAC-34 is also possible. The aerosol can contain a volatile solvent
or propellant along with a non-volatile solvent plus one or more
penetration enhancers. Numerous propellants are known to those
skilled in the art and can be used with LAC-34 in aerosol sprays.
When ethanol is the volatile solvent, a pump spray will be required
to create an aerosol. When butane is used, the container/closure
system can be pressurized and only a metering valve is required to
create a useful aerosol administration system.
TABLE-US-00011 TABLE 12 Examples of aerosol formulations of LAC-34
(propellant driven or pump-driven) % w/w of Component Formulation
RS--, R-- or S-LAC-34 0.2 to 20.0 Propylene glycol 0.0 to 40.0
Surfactant 0.05 to 5.0 Polymer.sup.1 0.0 to 3.0 Antioxidants.sup.2
0.0 to 0.3 Preservatives.sup.3 0.0 to 0.5 Propellants.sup.4 0.0 to
40.0 Penetration enhancers.sup.5 0.0 to 50.0 Water/buffer q.s.
.sup.1Examples: Hydroxypropylcellulose, hydroxyethylcellulose,
carbomer .sup.2Examples: BHA, BHT .sup.3Examples: Methyl paraben,
propyl paraben, imidurea .sup.4Examples: Butane, isobutane,
propane, hydrofluoralkane (134a, 227) .sup.5Examples: DMSO,
diethylene glycol monoethyl ether, n-decyl methyl sulfoxide,
dimethylacetamide, laurocapram (Azone .RTM.), dimethylformamide,
sucrose monooleate, N-methyl-2-pyrrolidine (Pharmasolve .RTM.), and
oleic acid
[0096] The aerosols will preferably contain from 0.1 percent to 30
percent of 2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an
optically active isomer thereof, in its free base form or as a
pharmaceutically acceptable salt.
[0097] Capsaicin (0.01% to 1.0%; w/w) can be included in these
formulations to obtain prolonged relief from pain and in particular
from neuropathic pain. The compound LAC-34 will inhibit or decrease
the initial pain caused by capsaicin. Other capsaicinoids, such as
dihydrocapsaicin, nordihydrocapsaicin, homocapsaicin and
homodihydrocapsaicin can also be used in analogous amounts, as can
the partial capsaicin receptor antagonist capsazepine and other
compounds that directly or indirectly influence ionic flow in
neuron membranes.
EXAMPLE 17
Methods of Manufacture: Aerosols
[0098] If the product is a pump spray, prepare solution as
described in the solutions/gels section and fill into the
appropriate container/closure system with spray pump.
[0099] If the product is a propellant-driven spray, dissolve LAC-34
in liquefied propellant and add appropriate solvents, penetration
enhancers, and surfactants/polymers. Mix until homogeneous then
fill under pressure into the appropriate container/closure system.
Alternatively, LAC-34 plus solvents, surfactants/polymers, and
penetration enhancers can be combined at room temperature/pressure
then filled into an aerosol canister. After crimping the metering
valve in place, the propellant can be pressure-filled into the
container.
[0100] Alternatively, the acrylic polymer or copolymer is dissolved
in the chosen vehicle; the active ingredient together with the
permeation enhancer is dissolved in the solution, the plasticizer
and remaining ingredients are added, the cans are filled, the
liquefied propellant is added and the metering valve is crimped in
place.
[0101] The racemic form of LAC-34 or an optically active isomer
thereof can be used for aerosols. The free base or a suitable salt
form can be used.
[0102] The aerosols will preferably contain from 0.1 percent to 30
percent of 2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an
optically active isomer thereof, in its free base form or as a
pharmaceutically acceptable salt.
EXAMPLE 18
A. Parenteral Formulations for LAC-34, Useful for Local Anesthesia
and for Analgesia after Injection
[0103] As a local anesthetic, LAC-34 is significantly more active
than lidocaine. Thus, the affinity of LAC-34 and lidocaine for the
Na.sup.+ channel (site 2) in the rat cerebral cortex was determined
and the inhibitory concentrations of the two local anesthetics were
determined. Membrane homogenates of cerebral cortex (250 .mu.g
protein) were incubated, in the absence or presence of the test
compound, for 60 min at 22.degree. C. with 10 nM
[.sup.3H]batrachotoxin. Nonspecific binding was determined in the
presence of 300 .mu.M veratridine.
[0104] IC50-values for inhibition of batrachotoxinin binding were
2.7E-7M and 4.7E-5M for LAC-34 and lidocaine, respectively, which
demonstrates that LAC-34 is significantly more effective as a local
anesthetic than lidocaine. It is concluded that LAC-34 may be
useful in lower concentration than lidocaine or, if used in
concentrations similar to lidocaine, the anesthetic depth and the
anesthetic duration will be more advantageous for LAC-34 than for
lidocaine.
[0105] Formulations for injection will preferably contain a
watersoluble salt of LAC-34, such as for example the LAC-34
dihydrochloride salt. It was found that this salt is highly water
soluble. This salt also binds molecular water.
[0106] Surprisingly, and contrary to lidocaine, LAC-34 was found
not to cause local vasodilatation at the dermal injection site. It
is assumed that the surprisingly long duration of local anesthetic
activity of LAC-34 may at least in part be due to the lack of
vasodilating effects of this compound. It was, however found that
the long duration of local anesthetic activity could be further
prolonged by incorporation of a vasoconstrictor, such as
epinephrine in concentrations usually used for epinephrine in
combinations with local anesthetics, such as lidocaine, and well
known to those skilled in the art of medicine.
[0107] Since local anesthetics for injection should preferably be
water soluble, the free base of LAC-34 is less favored than
water-soluble salts, such as for example the dihydrochloride salt
of LAC-34. Excipients included in a solution for injections of
LAC-34.times.2HCl are shown in Table 13.
TABLE-US-00012 TABLE 13 Formulations of LAC-34 for injections % w/w
of Component Formulation RS--, R-- or S-LAC-34 .times. 0.1 to 10.0
2HCl Chelating agents.sup.1 0.0 to 0.3 Antioxidants.sup.2 0.0 to
0.3 Preservatives.sup.3 0.0 to 0.5 Vasoconstrictors.sup.4 0.00 to
0.05 Water/buffer q.s. .sup.1Examples: Disodium edetate, citric
acid .sup.2Examples: BHA, BHT, ascorbic acid .sup.3Examples: Methyl
paraben, propyl paraben, imidurea .sup.4Examples: Epinephrine,
phenylephrine
[0108] The solutions for parenteral use will preferably contain
from 0.1 percent to 30 percent of
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an optically
active isomer thereof, preferably as a water-soluble,
pharmaceutically acceptable salt.
[0109] Capsaicin (0.01% to 1.0%; w/w) can be included in these
formulations to obtain prolonged relief from pain and in particular
from neuropathic pain. The compound LAC-34 will inhibit or decrease
the initial pain caused by capsaicin.
[0110] Other capsaicinoids, such as dihydrocapsaicin,
nordihydrocapsaicin, homocapsaicin and homodihydrocapsaicin can
also be used in analogous amounts, as can the partial capsaicin
receptor antagonist capsazepine and other compounds that directly
or indirectly influence ionic flow in neuron membranes.
EXAMPLE 19
Methods of Manufacture: Parenteral Solutions
[0111] Combine ingredients, including active, in an appropriate
vessel and mix until homogeneous. Aseptically filter and fill the
solution into the appropriate container/closure system. Terminal
sterilization is also an option in the drug product preparation if
required.
[0112] The racemic form of LAC-34 or an optically active isomer
thereof can be used. The free base or (preferably) a water-soluble
salt form can be used.
[0113] The solutions for parenteral use will preferably contain
from 0.1 percent to 30 percent of
2-[2-(N-phenyl-N-2-indanyl)aminoethyl]piperidine, or an optically
active isomer thereof, preferably as a water-soluble,
pharmaceutically acceptable salt.
EXAMPLE 20
Pharmacological Comparison Between Dermal Anesthetic Activity of
the Free Base and Various Salt Forms
[0114] The purpose of this study was to determine the degree to
which various salt forms of LAC-34 contribute to the local dermal
anesthetic effect of the compound, following dermal application to
guinea pigs.
[0115] Four groups of six male guinea pigs received a dose of 2.0
ml of a 5.0% solution of four test articles (LAC-34 base, LAC-34
mono-HCl, LAC-34-di HCl and LAC-34 mesylate) that had been applied
onto a two inch square, 4 layer thick gauze pad on depilated dosal
skin of each guinea pig. Similarly, one group of guinea pigs
received the vehicle, which consisted of DMSO/water (90 percent/10
percent, v/v) and served as the control group. The gauze was
occluded and the guinea pigs were wrapped for 30 min. Animals were
assessed for initial pain reaction (anesthetic depth) at 15 minute
intervals up to 3 hours and at 24 hours. An algesimeter, set at 10
g, was employed to assess the onset and depth of anesthesia using
the pinprick method causing a twitch response or non-response. The
"Average Anesthetic Score" was defined as number of probings not
producing a dermal twitch response. Thus, a situation where there
were no dermal twitch responses to six probings represent a maximal
anesthetic effect and is denoted as an Average Anesthetic Score of
6.
RESULTS
[0116] The Average Anesthetic Scores after patch removal are shown
in Table 13 (vales have been claculated from Table 1 in the
original Report.)
TABLE-US-00013 TABLE 13 Average Anesthetic Scores after patch
removal. Time after Patch Treatment Removal (min) Group 15 30 60 90
180 LAC-34 Free Base 4.8 4.8 4.4 3.3 2.2 LAC-34 Mono-HCl 0.2 0.8
1.3 0.7 0.7 LAC-34 Di-HCl 1.0 1.0 2.3 0.8 0.2 LAC-34 Mesylate 0.7
0.7 1.8 1.5 0.2 Vehicle 0.0 0.0 0.0 0.0 0.0
[0117] The results shown in the table 13, demonstrate a favorable
effect LAC-34 base when compared with the salt forms tested here.
The duration of anesthesia was longer for the free bas than for any
of the salts and the maximal depth of anesthesia (4.8 for LAC-34
base) was more favorable than for any of the salt forms (2.3 for
LAC-34 dihydrochloride)
CONCLUSION
[0118] The dermal anesthetic activity of LAC-34 free base was
significantly more pronounced that that of any of the LAC-34 salt
forms.
[0119] When used to treat pain, LAC-34 can be administered
dermally, topically, parenterally or orally. The doses and the
frequency of the drug administration depend on the size and age of
the patient, the severity of the condition, the administration
form, and the results that may be expected. Dermal or topical doses
of 10 to 500 mg, intravenous doses of from 1 to 100 mg and oral
doses of 5 to 200 mg administered one to four times daily may be
useful for patients from suffering from these conditions.
EQUIVALENTS
[0120] Those skilled in the art will realize that liposome
formulations containing LAC-34 and the isomers thereof may be
clinically useful. There is a wide variety of liposomes available
and using no more than routine experimentation, those skilled in
art may develop clinically useful formulations containing LAC-34
and suitable liposome suspensions. All equivalents are intended to
be encompassed in the scope of the present invention.
[0121] All doses indicated in this document refer to human doses.
For use in animals, the doses may be the same as human doses or may
be lower or higher, depending on the species and the reason for the
treatment. The animal caretaker or a veterinarian will be able to
determine the useful dose and concentration that is preferred to
specific animals.
[0122] Doses higher or lower than indicated here may be useful in
humans or in animals and all useful dose levels are intended to be
encompassed in the scope of this invention.
* * * * *